Moo I L-ý4 G ýý a
`
`J. Fernandes J.-M. Saudubray G. Van den Berghe Eds.
`
`Inborn Metabolic Diseases
`
`Diagnosis and Treatment
`
`BAmSN 1ARA
`DOCUMENT PPLy CENTR$
`
`3rd Revised Edition
`
`With 66 Figures and 57 Tables
`
`Springer
`
`EXHIBIT
`
`Z
`
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`

`

`Dr. JOHN FERNANDES
`Professor Emeritus of Pediatrics
`
`Veldweg 87
`8051 NP Hattem The Netherlands
`
`Professor JEAN-MARIE SAUDUBRAY
`Hospital Necker-Enfants Malades
`149 Rue de Sevres
`75743 Paris Cedex 15 France
`
`Professor GEORGES VAN DEN BERGHE
`Christian de Duve
`Institute of Cellular Pathology
`Universite Catholique de Louvain
`Avenue Hippocrate
`i2oo Brussels Belgium
`
`75
`
`Cover
`
`illustration Putti by delta Robbia at Spedale degli
`
`Innocenti Firenze Italy
`
`ISBN 3-54o-65626-XSpringer-Verlag Berlin Heidelberg New York
`
`ISBN 3-540-58546-X.
`
`2d edition Springer-Verlag Berlin Heidelberg New York
`
`Library of Congress Cataloging in Publication Data applied for.
`Die Deutsche Bibliothek - CIP-Einheitsaufnahme
`Inborn metabolic diseases diagnosis and treatment/l. Fernandes...
`London Milano Paris Singapore Springer 2000.
`ISBN 3-54o-65616-X
`
`- 3.
`
`rev. ed. - Berlin Heidelberg New York Barcelona Hong Kong
`
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`

`

`The Urea Cycle
`
`in the liver is the main pathway for the
`The urea cycle which in its complete form is only present
`disposal of excess of ammonium nitrogen. This cycle
`in the
`sequence of reactions localised in part
`the toxic ammonia molecule
`mitochondria and in part
`into the non-toxic
`in the cytosol converts
`product urea which is excreted in the urine. There are genetic defects of each of the enzymes of the
`urea cycle which lead to hyperammonaernia. Some genetic defects of other
`important metabolic
`the urea cycle. Alternative pathways
`inhibition of
`pathways may lead to secondary
`for nitrogen
`excretion namely conjugation of glycine with benzoate and of glutamine with phenylacetale can be
`exploited in the treatment of patients with defective ureagenesis.
`
`Phony butyrato
`
`HEPATIC NITROGEN
`POOL
`
`PhenyieutyryrCoA
`
`Pheny/acerato
`
`Gltttamine
`
`Alanine
`
`Aspartate
`
`Glycine
`
`Glutamate
`
`Acotyl CoA 0
`
`N-acetyl
`glutamate
`
`Glutamine
`
`Phenylacetyt-glutamine
`
`Benzoaro
`
`Benroyl CoA
`
`Glycine
`
`0 Hippurate
`
`NH3
`
`0
`
`Carbamoyl
`phosphate
`
`mitochondr/on
`
`Citrutline
`
`Ornlthlne
`
`A.apartate
`
`Citrulttne
`
`Ornithino
`
`Q
`Argtnino-Urea
`succinate Q
`
`-.V-Arginine
`
`cytoSOý
`
`arctic acid
`
`orotidlne
`
`tumarate
`
`Urine
`
`Fig. 17.1. The urea cycle and alternative pathways of nitrogen excretion. Enzymes
`i. carbamoyl
`phosphate
`synthetase
`argininosuccinate synthetase 4 argininosuccinate vase s arginase 6 Nacetyiglutamate
`2. ornithine transcarbamoylase
`synthetase. Enzyme defects are depicted by solid bars across the arrows
`
`This article is protected by copyright and is provided by Wisconsin
`
`TechSearch
`
`under license
`
`from Wolters Kluwer Health. All rights reserved.
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`
`

`

`CHAPTER 17
`
`Disorders of the Urea Cycle
`
`J.V. Leonard
`
`CONTENTS
`
`Clinical Presentation
`
`precip-Toxicity
`devel-General
`psychoso-Prognosis
`
`Patients with
`
`at
`
`disorders may present
`urea-cycle
`almost any age. However
`there are certain times at
`which they are more likely
`symptoms
`to develop
`because of metabolic stress such as infection
`
`itating protein catabolism. These are
`
`The neonatal period.
`During late infancy. Children are vulnerable during
`this period because of
`the slowing of growth the
`to cows milk and weaning foods and the
`change
`declining maternal antibody and consequent
`opment of intercurrent infections.
`Puberty. The changing growth rate and
`factors may precipitate decompensation.
`cial
`
`Clinical Presentation ...........................
`Neonatal Presentation .........................
`Infantile Presentation .........................
`Children and Adults ..........................
`Metabolic Derangement
`........................
`...................................
`Diagnostic Tests ..............................
`Biochemical Tests ............................
`Imaging ...................................
`Differential Diagnosis .........................
`Treatment ...................................
`...........................
`Low-Protein Diet
`Essential Amino Acids ........................
`for Nitrogen Excretion .......
`Alternative Pathways
`Aspects of Therapy ....................
`for Treatment .....................
`Assessment
`Emergency Treatment .........................
`....................................
`and Prenatal Diagnosis ..................
`
`Genetics
`
`215
`
`215
`216
`
`216
`
`216
`
`217
`
`217
`
`217
`
`218
`
`21s
`
`2t8
`
`218
`
`219
`
`219
`
`a19
`
`220
`
`220
`
`221
`
`221
`
`References
`
`....................................
`
`a1
`
`Five inherited disorders of
`
`the urea cycle are now
`well described. These are characterised
`by hyper-
`
`con-overwhelming
`
`amino-acid metabo-
`
`illness that
`
`ammonaemia
`and disordered
`lism. The presentation
`is highly variable those
`presenting in the newborn
`an
`period usually have
`rapidly progresses from
`and
`poor feeding vomiting lethargy or irritability
`tachypnoea to fits coma and respiratory arrest.
`In
`and more
`infancy the symptoms are less severe
`variable. Poor developmental
`progress behavioural
`problems hepatomegaly and gastrointestinal
`symp-
`and adults
`toms are usually observed.
`In children
`chronic
`
`the
`
`clinical
`
`rather
`
`characteristic
`
`are
`
`is
`
`is
`
`in
`
`However
`it must be emphasised that many patients
`may present outside these periods. The patterns of
`presentation of hyperammonaemia
`and are broadly similar for all
`which
`the disorders except
`arginase deficiency
`discussed separately. The early symptoms are often
`and
`initially therefore the diagnosis
`non-specific
`The most
`easily overlooked.
`important
`points
`are to think of it during
`diagnosing hyperammonaemia
`diagnosis and to measure the plasma ammonia
`centration.
`
`Neonatal Presentation
`
`interval
`
`Most babies with urea cycle disorders are of normal
`healthy but after
`a short
`and are initially
`birthweight
`that can be less than 24 h they become unwell.
`Common early symptoms are poor feeding vomiting
`and tachypnoea. The initial
`lethargy and/or
`irritability
`invariably sepsis. Rather
`working diagnosis is almost
`characteristically these babies may have
`mild respiratory alkalosis which
`can
`this stage. Usually they deteriorate
`diagnostic clue at
`rapidly with more obvious neurological and autonomic
`tone with loss of
`of
`problems including changes
`instability and hypother-
`normal
`reflexes vasomotor
`
`a transient
`
`be
`
`a useful
`
`behavioural
`
`irritability
`
`illness
`
`is
`
`characterised
`
`by
`and
`
`neurological
`problems confusion
`cyclic vomiting which deteriorates to acute encepha-
`lopathy during metabolic stress. Arginase deficiency
`symptoms such
`shows more specific
`as spastic
`diplegia dystonia ataxia and fits. All
`inheritance ex-
`disorders have autosomal-recessive
`
`ornithine carbamoyl
`cept
`which is X-linked.
`
`transferase deficiency
`
`urea-cycle
`
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`
`

`

`216
`
`Chapter 17
`
`mia apnoea and fits. The baby may soon become totally
`and may require full
`intensive
`unresponsive
`Untreated most babies will die often with complica-
`
`care.
`
`tions such as cerebral or pulmonary haemorrhage the
`for which may not be
`underlying metabolic
`cause
`recognised. Some survive neonatal hyperammonaemia
`to some degree.
`are invariably handicapped
`
`psycho-but
`
`continue to have problems such as vomiting or poor
`progress. Some patients may voluntarily
`developmental
`In addition to those
`their protein intake.
`restrict
`disorders already mentioned the illness may be attrib.
`uted to a wide variety of other disorders including
`Reyes syndrome encephalitis poisoning and
`social problems.
`
`Infantile Presentation
`
`specific
`
`the illness
`
`is
`
`rather
`the symptoms are generally
`less
`in infancy
`acute and more variable than in the neonatal period
`and include anorexia lethargy vomiting and failure to
`thrive with poor developmental
`progress.
`Irritability
`and behavioural problems are also common. The liver
`enlarged but
`is often
`as the symptoms are rarely
`attributed to many
`initially
`include gastrointestinal disorders
`reflux cows milk protein intoler-
`gastro-oesophageal
`food allergies behaviour problems or hepatitis.
`The correct diagnosis is often only established when
`the patient develops a more obvious
`encephalopathy
`level and neurological
`in consciousness
`changes
`signs see below
`
`different causes that
`
`pre-ance
`pro-with
`
`CHRONIC NEUROLOGICAL
`
`or
`ILLNESS. Learning difficulties
`retardation are common and
`more obvious mental
`some patients particularly those with argininosuccinic
`few symptoms
`aciduria may present with relatively
`from mental retardation and fits. About half the
`apart
`patients with argininosuccinic
`acid have brittle hair
`trichorrhexis nodosa. Patients may present with
`ataxia which
`chronic
`is worse during intercurrent
`
`infections
`
`131.
`
`DF.FICIENCY. Arginase deficiency commonly
`ARGINASE
`sents with spastic diplegia and initially a diagnosis of
`cerebral palsy is almost always suspected. However the
`to be slowly
`abnormalities appear
`neurological
`gressive although it may be difficult
`to distinguish this
`from an evolving cerebral palsy. During the course of
`fits ataxia and dystonia may develop.
`the disease
`Occasionally patients may present with
`an
`acute
`fits 4.
`encephalopathy or anticonvulsant-resistant
`
`Metabolic Derangement
`
`Children and Adults
`
`At
`
`these ages the patients commonly present with a
`more obviously neurological
`illness.
`
`pres-ent
`
`ACUTE EICEPHALOPATHY. Whilst older patients often
`The urea cycle is the final common pathway
`with episodes of acute metabolic encephalopathy
`for the
`excretion of waste nitrogen in mammals. The steps in
`they may also have
`chronic
`symptoms. Usually
`the urea cycle are shown in Fig. 17.1. Ammonia is
`symptoms develop following metabolic
`stress precip-
`from glutamine and
`itated by infection anaesthesia or protein catabolism probably derived
`principally
`glutamate and is converted
`such as that produced by the rapid involution of the
`phosphate
`to carbamoyl
`synthetase CPS.
`in the puerperium t. However
`an obvious
`uterus
`This
`by
`carbamoyl phosphate
`The patients
`is not always apparent.
`enzyme requires an allosteric activator
`and unwell. Sometimes
`mate for full activity. This compound is formed by the
`anorexic lethargic
`of acetyl coenzyme A acetyl CoA and
`they are agitated and irritable with behaviour prob-
`condensation
`erns or confusion. Vomiting and headaches may be
`glutamate in a reaction catalysed by N-acetyl glutamate
`synthetase. Carbamoyl phosphate condenses with
`prominent suggesting migraine or cyclical
`vomiting.
`On
`nithine to form citrulline in a reaction catalysed by
`may
`be ataxic
`intoxicated.
`though
`as
`examination hepatomegaly may be present particu-
`The product citrulline
`ornithine transcarbamoylase.
`The
`larly in those with argininosuccinic
`condenses with aspartate to produce argininosuccinate
`aciduria.
`patients may then recover completely but if not they
`in a reaction catalysed by argininosuccinate
`synthetase
`and the arginosuccinate
`may then develop neurological
`problems including a
`is then hydrolysed to arginine
`and some-
`and fumarate by argininosuccinate
`lyase. The arginine
`fluctuating level of consciousness
`signs such as hemiplegia z is
`and
`times focal neurological
`by arginase releasing
`cleaved
`itself
`or cortical blindness. Untreated they continue
`re-forming ornithine. Within the urea cycle itself
`comatose and they may die.
`is neither formed nor lost.
`deteriorate becoming
`ornithine acts as a Carrier it
`they may
`recover with a significant
`The cause of death is usually
`neurological deficit.
`cerebral oedema.
`Between episodes the patients are usually relatively
`some particularly younger ones may
`
`trigger
`
`Nacetylgluta-become
`
`or-Others
`
`first
`
`Alternatively
`
`well although
`
`fits
`
`to
`
`urea
`
`Each molecule of urea contains two atoms of waste
`nitrogen one derived from ammonia and the other
`from aspartate. Regulation of the urea cycle is not
`understood and it
`there are several
`is likely that
`mechanisms controlling flux through this pathway 51.
`
`fully
`
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`
`

`

`Disorders of the Urea Cycle
`
`217
`
`it
`
`Some of the symptoms of hyperammonaemia
`can be
`explained on this basis and the dietary tryptophan
`restriction has reversed anorexia in some patients with
`urea cycle disorders 181. Ammonia induces many other
`electrophysiological vascular and biochemical
`changes
`is not known to what
`in experimental systems but
`all of
`to the problems of
`extent
`these are relevant
`in man 9.
`clinical hyperammonaemia
`Using proton nuclear magnetic resonance
`copy glutamine can also be shown to accumulate
`both in experimental models and
`high concentrations
`in man in vivo fol. The concentrations
`are such that
`the increase in osmolality could be responsible
`cellular swelling and cerebral oedema.
`
`at
`
`for
`
`Diagnostic Tests
`
`Biochemical Tests
`
`Routine
`
`tests
`
`are not helpful
`
`the
`
`for establishing
`of
`Plasma
`hyperammonaemia.
`diagnosis
`aminases may be elevated combined with
`diagnosis of
`to the erroneous
`galy this may lead
`
`spectros-catabolism
`en-zyme
`trans-the
`
`These include enzyme induction the concentrations of
`and N-acetyl glutamate and
`substrates intermediates
`hormonal effects. Defects of each step have now been
`described and are listed in Table 17.1.
`The plasma ammonia concentration
`is raised as a
`result of metabolic blocks in the urea-cycle. The degree
`is elevated depends on several
`to which
`factors
`including the enzyme involved and its residual activity
`the protein intake and the rate of endogenous protein
`this is increased because of
`particularly if
`infection fever or other metabolic stresses. The values
`may also be falsely elevated
`collected and handled correctly.
`The
`the amino acids
`concentrations
`of
`
`if
`
`the specimen is not
`
`in the
`
`it
`
`metabolic
`
`defect will
`
`to the
`pathway immediately proximal
`increase and those beyond the block
`will decrease Table 17.1.
`In addition plasma alanine
`and particularly glutamine accumulate
`disorders. The
`concentration
`of cirrulline is often
`
`in all
`
`the
`
`it may not always be reliable during the
`helpful but
`newborn period 61.
`Orotic acid and orotidine are excreted in excess
`
`in
`
`to the
`
`urine if
`there is a metabolic block distal
`as is the case in
`of carbamoyl phosphate
`ornithine transcarbamoylase OTC deficiency
`cit-
`aciduria and arginase
`rullinaemia argininosuccinic
`In these disorders carbamoyl
`deficiency Fig. 17.1.
`leaves the mitochondrion and
`phosphate accumulates
`once in the cytosol enters the pathway for the de novo
`synthesis of pyrimidines. The urea cycle is also closely
`linked
`of
`to many other pathways
`intermediary
`metabolism particularly the citric-acid cycle.
`
`hepatome-formation
`
`a
`
`concentra-tions
`
`hepatitis.
`The most
`in urea cycle
`test
`important diagnostic
`disorders is measurement
`the plasma ammonia
`of
`concentration. Normally this is less than 50 pmol/I but
`may be slightly raised as
`result of a high protein
`a haemolysed
`intake exercise
`struggling or
`blood
`sample. Generally patients who are acutely unwell with
`urea cycle disorders have plasma ammonia
`than 150 pmol/l and often significantly
`greater
`the concentrations
`may be near
`higher. However
`normal when patients are well are early in an episode
`been on a
`of decompensation
`they have
`or
`intake for some time.
`protein high-carbohydrate
`Healthy neonates have slightly higher values ttj.
`they are ill sepsis perinatal asphyxia etc. plasma
`
`low-Ammonia
`
`Toxicity
`
`increases the transport of tryptophan
`the blood-brain barrier which
`then leads to an
`and release of serotonin
`increased
`
`production
`
`71.
`
`across
`
`if
`
`If
`
`Table 17.1. Urea-cycle disorders biochemical and genetic details
`
`Disorder
`
`Alternative names
`
`Plasma amino
`
`CPS deficiency
`
`CPS deficiency
`
`OTC deficiency
`
`OTC deficiency
`
`Argininosuccinic
`
`synthetase
`
`deficiency
`
`Argininosuccinic
`lyase deficiency
`
`Citrullinacmia
`
`Argininosuccinic
`aciduria
`
`Arginase deficiency
`NAGS deficiency
`
`Hyperargininaemia
`NAGS deficiency
`
`acid concentrations
`
`T alanine
`T Glutamine
`I citrulline I arginine
`T Glutamine
`T alanine
`I citrullinc I arginine
`TT Citrulline .
`arginine
`
`T Citrulline
`T
`argininosuccinic acid
`1. arginine
`T Arginine
`T Glutamine T alanine
`
`Urine
`orotic acid
`
`Tissue for enzyme
`
`diagnosis
`
`Genetics chromosome
`localisation
`
`N
`
`TT
`
`T
`
`T
`
`T
`N
`
`Liver
`
`Liver
`
`AR chromosome 2p
`
`X-linked Xp21.1
`
`Liver/fibroblasts
`
`AR chromosome 9q
`
`RRCIliverl
`
`fibroblasts
`
`RBC/liver
`
`Liver
`
`AR chromosome 7q
`
`AR chromosome 6q
`AR not confirmed
`
`T.
`
`recessive CPS carbamyl phosphate synthetase N normal NAGS N-acetylglutamate
`increased 1 decreased AR autosomal
`synthetase OTC ornithine transcarbamoylase RBC red blood cell
`
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`
`

`

`218
`
`Chapter 17
`
`ammonia concentrations may increase to 18o pmol/l.
`Patients with inborn errors presenting in the newborn
`have
`than
`concentrations
`greater
`period usually
`very much greater.
`In that case
`200 tmol/1 often
`particularly of
`the plasma
`further
`investigations
`amino acid and urine organic acid levels are urgent.
`should be performed
`The following investigations
`
`Blood pH and gases
`Plasma chemistry sodium urea and electrolytes
`glucose and creatinine
`Liver-function tests and clotting studies
`Plasma amino acids
`Urine organic acids Drone acid and amino acids
`Plasma free and acyl carnitines
`
`of
`
`ar-
`
`In all urea-cycle disorders there is accumulation
`and in citrullinaemia
`glutamine and alanine
`gininosuccinic aciduria and arginase deficiency the
`in the amino acids are usually diagnostic
`changes
`Table 17.1. Orotic aciduria with raised plasma gluta-
`suggests OTC deft-
`mine and alanine concentrations
`ciency. The diagnosis of this and the other disorders
`can be confirmed by measuring enzyme activity in
`appropriate tissue Table 17.1. The enzyme diagnosis
`is not
`deficiency
`of N-acetyl
`synthetase
`
`load of
`
`glutamate
`and
`the
`to
`a
`response
`straightforward
`N-carbamyl glutamate an orally active analogue of
`N-acetyl glutamate may be helpful both diagnostically
`and for treatment.
`
`Table 17.2. Differential diagnosis of hyperammonaemia
`
`Argininosuccinate
`
`inherited disorders
`Urea cycle enzyme defects
`Carbamoyl phosphate synthetase deficiency
`Ornithine transcarbamoylase deficiency
`synthetase deficiency citrullinaemia
`aciduria
`
`lyase deficiency arginosuccinic
`
`Argininosuccinate
`Arginase deficiency
`N-acetylglutamate synthetase deficiency
`Transport defects of urea cycle intermediates
`Lysinuric protein intolerance
`Hy-hyperornithinemia-homocitrullinuria
`syndrome
`Organic acidurias
`Propionic acidaemia
`acidaemia and other organic acidaemias
`Methylmalonic
`Fatty acid oxidation disorders
`Medium-chain
`acyl-CoA dehydrogenase deficiency
`Systemic carnitine deficiency
`Long-chain fatty acid oxidation defects and other
`disorders
`
`related
`
`form
`
`Other inborn errors
`Pyruvate carboxylase deficiency neonatal
`Acquired
`Transient hyperammonemia of the newborn
`Reyes syndrome
`failure any cause both acute and chronic
`Liver
`Valproate therapy
`Infection with urcase-positive bacteria particularly with
`stasis in the urinary tract
`Leukaemia therapy including treatment with asparaginase
`in neonates
`Severe systemic illness particularly
`
`CoA coenzyme A
`
`hype-rammonaemia
`
`transient
`
`prema-Imaging
`
`or ketosis. Although babies with
`of the newborn are often born
`turely with early onset of symptoms 131 it may be
`to distinguish between urea-cycle disorders
`and transient hyperammonaemia of the newborn. All
`in whom a
`diagnosis of Reyes
`tentative
`patients
`syndrome is made should be investigated
`in detail
`for inherited metabolic disorders including urea-cycle
`disorders.
`
`difficult
`
`Patients who present with an acute encephalopathy
`This
`commonly receive brain imaging at an early stage.
`may show no abnormality a localised area of altered
`signal or if the patient
`is very seriously ill widespread
`cerebral oedema 121.
`Focal areas of altered signal may be identified and
`need to be distinguished from herpes simplex enceph-
`alitis. A careful history revealing previous episodes of
`albeit mild may provide vital clues.
`encephalopathy
`Imaging in patients who have recovered from a severe
`episode of hyperammonaemia usually show cerebral
`atrophy that may be focal particularly in those areas in
`which
`there were altered signals during the acute
`
`illness.
`
`Differential Diagnosis
`
`The differential diagnosis
`of hyperammonaemia is
`wide and the most common conditions are summa-
`In the neonatal period the most
`rised in Table 17.2.
`common differential diagnoses are organic acidaemias
`particularly propionic and methylmalonic acidaemia.
`Patients with these disorders may have had marked
`hyperammonaemia with minimal metabolic
`acidosis
`
`-
`
`Treatment
`
`The aim of
`
`treatment
`
`is to correct
`
`the biochemical
`
`disorder and to ensure that all
`the nutritional needs are
`met. The major strategies used are to reduce protein
`pathways of nitrogen
`intake to utilise
`alternative
`excretion and to replace nutrients that are deficient.
`
`Low-Protein Diet
`
`require a low-protein diet. The exact
`Most patients
`quantity will depend mainly on the age of
`the patient
`the disorder. Many
`and the severity of
`published
`severe protein restriction but
`regimens suggest
`or
`patients may need
`1.8-2 g/kglday
`early infancy
`more during phases of very rapid growth. The protein
`intake usually decreases to approximately 1.2-1.5 g/kg/
`years and 1 g/kg/day
`in late
`
`day during pre-school
`
`in
`
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`Page 7 of 11
`
`

`

`the quantity of natural
`childhood. After puberty
`However
`may be less than o.5 g/kg/day.
`must be emphasised that
`there is considerable
`tion in the needs of individual patients.
`
`varia-
`
`it
`
`Essential Amino Acids
`
`nones-protein
`defi-achieve
`vari-patients
`
`ARr1v1NE AND CITRULLIUE Arginine is normally a
`sential amino acid because
`is synthesised within the
`urea cycle. For this reason all patients with urea-cycle
`those with arginase deficiency are
`disorders except
`likely to need a supplement of arginine to replace that
`which is not synthesised 181. The aim should be to
`between
`arginine concentrations
`maintain plasma
`so pmol/l and 200 mol/I. For OTC and CPS
`a dose of 100-I50 mg/kg/day
`appears
`for most patients. However.
`in severe
`ants of OTC and CPS. citrulline may be substituted for
`arginine in doses up to 170 mg/kg/day.
`as this will
`utilise an additional nitrogen molecule. Patients with
`and argininosuccinic aciduria have
`
`Disorders of the Urea Cycle
`
`219
`
`it
`
`to be
`
`ciencies.
`
`sufficient
`
`citrullinaemiu
`
`a
`
`In the most severe variants it may not be possible to
`good metabolic control and satisfactory nutri-
`Lion with restriction of natural protein alone. Other
`In
`will not
`take their full protein allowance.
`these groups of patients some of
`the natural
`both
`protein may be replaced with an essential amino acid
`mixture giving
`Using this the
`up to 0.7 g/kg/day.
`requirements for essential amino acids can be met in
`addition waste nitrogen is re-utilised to synthesise
`amino acids hence
`reducing the load of
`
`higher requirement. because ornithine is lost as a result
`administer-non-essential
`of the metabolic block this is replaced by
`ing arginine. Doses of up to 700 mg/kg/day may be
`needed
`this does
`of
`but
`have
`the disadvantage
`the concentrations of citrulline and
`ar-gininosuccinate.
`respectively. The consequences of this
`to be less important
`than those caused by
`are thought
`the accumulation ofammonia and glutamine.
`
`waste nitrogen.
`
`increasing
`
`Alternative Pathways
`
`for Nitrogen Excretion
`
`N-acetyl-introduced
`too-excreted.
`
`OTHER MEDICATION. Citrate has long been used to provide
`is known
`a supply of Krebs-cycle intermediates 19. It
`to reduce postprandial elevation of ammonia and may
`be helpful
`of argininosuccinic
`in the management
`aciduria zol.
`N-carbamyl glutamate can be used
`to replace the missing
`glutamate synthetase deficiency
`is active orally. The dose is
`compound as
`300 mg/kg/day 2t. Patients who respond may require
`treatment with this compound
`only. Anticonvulsants
`may be needed
`for patients with urea-cycle disorders
`but sodium valproate should not be used as this drug
`may precipitate fatal decompensation particularly in
`OTC patients 22.
`
`in
`
`it
`
`is necessary. A
`In many patients additional
`therapy
`in this field has been the development
`major advance
`that are conjugated to amino acids and
`of compounds
`rapidly excreted 114 Is. The effect of the administra-
`tion of these substances is that nitrogen is excreted in
`other than urea hence the load on the
`compounds
`urea cycle is reduced Fig. 17.1. The first
`compound
`was sodium benzoate. Benzoate is conju-
`gated with glycine to form hippurate which is rapidly
`For each mole of benzoate given i mol of
`nitrogen is removed. Sodium benzoate is usually given
`in doses up to 250 mg/kg/day but
`in acute emergen-
`The
`increased
`Gies this can be
`to 500 mg/kg/day.
`major side effects are nausea vomiting and irritability.
`may be incomplete with
`In neonates
`conjugation
`toxicity C. Bachmann personal
`increased
`risk of
`
`quanti-former
`
`in females. Other
`
`it.
`
`General Aspects of Therapy
`
`the
`
`All treatment must be monitored with regular
`tative estimation of plasma ammonia and amino acids
`of
`paying particular attention to the concentrations
`glutamine and essential amino acids. The aim is to keep
`plasma ammonia levels below 8o Etmol/l and plasma
`glutamine levels below Boo tmol/l 231.
`In practice a
`of iooo ppmol/I
`glutamine concentration
`together with
`of essential amino acids within the
`concentrations
`
`communication.
`The next drug used was phenylacetate
`but
`this has
`now been superseded by phenylbutyrate because
`has a peculiarly unpleasant clinging mousy
`In the liver phenylbutyrate is oxidised to
`odour.
`phenylacetate which is then conjugated with glutamine.
`The resulting phenylacetylglutamine is rapidly excreted
`in urine hence 2 mol of nitrogen are lost for each mole
`of phenylbutyrate given. Phenylbutyrate
`is usually
`given as the sodium salt
`in doses of 250 mg/kg/day
`normal
`range see the algorithm Fig. 17.2 is probably
`but has been given in doses of up to 650 mg/kg/day
`t6.
`In a recent study of the side effects 17 there was a high more realistic. All diets must of course be nutritionally
`complete and must meet
`requirements for growth and
`incidence of menstrual disturbance
`normal development.
`it was not easy
`problems included anorexia but
`to
`distinguish between the effects of the disorder and
`The concept of balance of diet and medicine is
`important. The protein intake of the patients varies
`those of the medicine. Patients are often reluctant
`to
`take the medicine and great
`ingenuity is sometimes
`and the figures
`have been given
`considerably
`that
`should be regarded only as a guide. The variation
`needed to ensure that
`the patient takes
`
`Par Pharmaceutical, Inc. Ex. 1026
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`Page 8 of 11
`
`

`

`Fig. 17.2. Guidelines for the management of
`disorders except
`patients with urea-cycle
`arginase deficiency. This is intended for
`use in patients who have been stabilised
`previously and should only be regarded as a
`guide as some patients may have individual
`requirements. For more detail and infor
`mation about doses please refer to the text.
`EAAs essential amino acids
`
`220
`
`Chapter 17
`
`Patient previously
`stabilised
`
`no
`
`Patients condition
`acutely unwell
`
`yes
`
`Emergency
`
`regimen
`
`IF
`
`Maintain
`
`plasma arginine
`50 - 200 irnot/l
`
`Plasma ammonia
`
`j
`
`pmotll
`
`80
`
`IF
`
`120
`
`80
`
`IF
`
`Plasma glutamine
`pmolA
`
`Plasma glutamine
`
`pmolll
`
`1000
`
`1000
`
`1000
`
`1000
`
`1
`
`plasma
`EAAs
`
`plasma
`EAAs
`
`1ý
`
`plasma
`
`EAAs
`
`IF
`
`plasma
`EAAs
`
`N
`
`low
`
`N
`
`N
`
`low
`
`N
`
`no
`
`Change
`
`low
`
`tmedieines
`
`low
`
`I
`
`Tmedicines
`and
`tprotein or
`EAA5
`
`Tprotein or
`EAAs
`
`check
`
`conditions
`
`plasma
`ammonia
`
`collected
`
`three-difficult
`with-have
`
`if
`
`reflects not only the residual enzyme activity but also
`factors including appetite and growth rate.
`many other
`Some patients have an aversion to protein so it can be
`them to take even
`their recommended
`to get
`intake. Consequently they are likely to need smaller
`doses of sodium benzoate and phenylbutyrate. Others
`to take more protein and this
`to be
`has
`prefer
`balanced by an increase in the dosages of benzoate
`and phenylbutyrate.
`Some will
`take
`not
`adequate
`quantities of sodium benzoate or sodium phenylbuty-
`rate and therefore their protein intakes necessarily
`to be stricter than would be needed if
`they took
`the medicines. Hence for each patient a balance must
`be found between their protein intake and the dose of
`their medicines to achieve good metabolic control.
`
`Assessment
`
`for Treatment
`
`to
`
`infection anaesthesia or surgery. For this reason all
`patients should have detailed instructions of what
`do when they are at risk. We routinely use a
`is off-colour the
`the patient
`If
`stage procedure
`1241.
`protein is reduced
`and more carbohydrate
`is given.
`If symptoms continue protein should be stopped and
`a high-energy intake given with their medication by
`day and night. However
`they cannot
`tolerate oral
`drinks and medicines are vomiting or are becoming
`they should
`go to a
`encephalopathic
`progressively
`hospital for assessment and intravenous therapy
`out delay. For further practical details see Dixon and
`also have a high
`Leonard
`should
`241. Patients
`intake before any anaesthesia or surgery.
`carbohydrate
`patients who
`are seriously ill with
`is urgent. The steps are
`treatment
`listed below and early treatment
`is essential Chap. 3.
`
`For
`
`hype-rammonaerniat
`
`All patients with urea cycle disorders are at
`acute decompensation with acute hyperammonaemia.
`This can be precipitated by different kinds of meta-
`large protein load
`bolic stress such
`fasting a
`
`risk of
`
`as
`
`Emergency Treatment
`
`The volumes which are given are related to age and the
`condition of
`should
`be
`the patient. Fluid volumes
`
`Par Pharmaceutical, Inc. Ex. 1026
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`Page 9 of 11
`
`

`

`N-acetyl-
`increased de novo synthesis of pyrimidines seeMet--
`investiga-
`defi-
`
`Dialysis.
`
`If hyperammonaemia is not controlled or
`immediately available ha-
`the medicines
`are not
`emofiltration or haemodialysis/haemodiafiltration
`should
`be
`started without
`delay. Alternatively
`peritoneal dialysis can be used but
`this is a less
`effective method for reducing hyperammonaemia.
`Treat other conditions sepsis fits etc..
`Monitor
`intracranial pressure with the usual mea-
`pressure and maintain
`reduce
`raised
`
`sures
`
`to
`
`pressure.
`
`counselling
`
`closely
`
`molecular-perfusion
`ar-gininosuccinic
`
`restricted if
`
`there
`
`is any
`
`concern
`
`about
`
`cerebral
`
`Genetics and Prenatal Diagnosis
`
`oedema.
`
`Disorders of the Urea Cycle
`
`221
`
`Stop protein intake.
`Give a high energy intake.
`
`2.
`
`line
`
`is
`
`is
`
`The genes
`enzymes except
`for urea-cycle
`glutamate synthetase have been mapped isolated and
`t. Orally a io-zo% soluble glucose polymer or b fully characterised
`1271. Many mutations have been
`described. The most common
`urea cycle disorder
`protein-free formula or
`OTC deficiency which is an X-inked d